Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes by increasing the number of islets of langerhans cells

ABSTRACT

The present invention relates to the use of at least one compound with inhibitory activity on kynurenine 3-hydroxylase, for the preparation of a medica ment for increasing the number of islets of Langerhans cells, which is intended especially for the prevention and/or treatment of diabetes.

The present invention relates to compounds with inhibitory activity onkynurenine 3-hydroxylase and in particular to their use as products forpharmaceutical use by increasing the number of islets of Langerhanscells in the case of patients in need thereof, especially for theprevention and treatment of diabetes and related its complicationsand/or related pathologies (obesity, hypertension, etc.).

Diabetes mellitus represents a very heterogeneous group of diseases allhaving a certain number of characteristics in common: elevation ofglycaemia and increased long-term risk of developing cardiovascularcomplications.

In 1985, according to the criteria of the WHO, two major types ofdiabetes are distinguished: insulin-dependent diabetes (IDD), whichinvolves the manifestation of immunological phenomena, andnon-insulin-dependent diabetes (NIDD), which were previously known astype-1 and type-2 diabetes, respectively (World Health Organization,1985). The diabetes is said to be insulin-dependent if its symptoms(thirst, polyuria, coma, etc.) are associated with hyperglycaemia andketosis: the administration of insulin is then vital from the earlystages of the disease. In the majority of other cases, even ifpersistence of the hyperglycaemia secondarily necessitates theadministration of insulin, the diabetes is considered asnon-insulin-dependent and is treated in general using oral antidiabeticagents. Non-insulin-dependent diabetes currently affects 110 millionpeople worldwide. This number shows no sign of decreasing, since it isforecast that 216 million people will be affected by 2010.

Maintaining a sugar balance requires strict coordination between theorgans (brain, liver, pancreas, muscles and adipose tissue mainly)involved in energy metabolism.

In non-insulin-dependent diabetes, the liver and the pancreas are themain participants. Specifically, it has been clearly demonstrated thatexcessive production of glucose by the liver is responsible for fastedhyperglycaemia in diabetics (Consoli et al., Diabetes, Vol. 38 (1989),550-557). Similarly, impairment in pancreatic function (number of isletsof Langerhans cells, secretion of insulin and glucagon in response toglucose) contributes to the development of postprandial hyperglycaemia(Polonsky et al., N. Engl. J. Med., 318 (1988), 1231-39).

Insulin-dependent diabetes is an autoimmune disease that destroys thebeta cells of the pancreas. This disease involves genetic factors (genesof the HLA (human leukocyte antigen) system and of insulin itself) andalso environmental factors of nutritional and/or viral origin.

In addition to the hyperglycaemia symptoms and the complicationsresulting therefrom, the two types of diabetes have in common a defectof pancreatic origin.

The pancreas is a mixed organ comprising exocrine tissue, the role ofwhich is the synthesis and secretion of the enzymes required fordigestion, and an endocrine tissue composed of several types of cells,the role of which is to synthesis and secrete the hormones involved inmaintaining carbohydrate homeostasis. The endocrine cells are groupedtogether in the exocrine pancreas in the form of small structures ofcomplex cellular organisation known as islets of Langerhans. Theseislets are composed of four major cell types:

beta cells, which secrete insulin

alpha cells, which secrete glucagon

delta cells, which secrete somatostatin

PP cells, which secrete pancreatic polypeptide.

The amount of circulating insulin is controlled by rapid changes in theamount of hormone released by individual beta cells as a function of thevariations in plasmatic glucose. However, a longer-term regulation alsoexists, which makes it possible to adapt the production of insulin bymeans of changes in the total mass of beta cells. The pancreas iscapable of adapting its mass of beta cells when the demand for insulinincreases. The increase in this demand is observed in physiological andphysiopathological situations in which there is a reduction in thebiological efficacy of insulin (insulin resistance). Besides an anomalyof secretion of pancreatic hormones (glucagon and insulin), aninsufficiency in the number of islets of Langerhans cells and moreparticularly of beta cells may also contribute towards the secretorydeficit and thus towards the establishment of hyperglycaemia in the caseof type I and 11 diabetics (Klöppel G. et al. Surv. Synth. Path. Res(1985), 4:110125). Several studies performed on animal models ofdiabetes show that the genetic terrain is an important parameter in thegrowth of beta cells (Andersson A., Diabetologia (1983); 25: 269-272;Swenne I. Diabetes, (1984), 32:14-19).

In the course of diabetes, three stages are distinguished in theevolution:

not requiring insulin

requiring insulin

insulin required for survival.

Separation of the description of the types of diabetes and of theirevolutive stages shows the importance of avoiding the assimilation ofinsulin-dependent diabetes and diabetes treated with insulin. However,for non-insulin-dependent diabetes, an early stage and a late stage areconventionally distinguished, relating to the duration and seriousnessof the diabetic condition.

The main treatment for type I diabetes consists of the subcutaneousinjection of insulin. The clinical manifestation of diabetes is alwayspreceded by a longer or shorter asymptomatic period known asprediabetes, during which organs can, however, become affected longbefore the diabetes is diagnosed.

In 2002, the American Diabetes Association suggested a new definition ofprediabetes, namely a condition characterised by blood glucoseconcentrations that are higher normal, but lower than thosecorresponding to the predefined criteria of diabetes. A normal glycaemicequilibrium is characterised by a fasting glycaemia of less than 1.10g/l and a glycaemia after meals of less than 1.40 g/l. If the fastingglycaemia is 1.26 g/l or greater and/or increases to more than 2 g/lafter meals, diabetes is diagnosed.

More specifically, the prediabetic condition corresponding to type Idiabetes may be defined by the presence of immunological markers, suchas those described by Buysschaert et al, Louvain Med. 119, S251-S258,2000, especially including the anti-islet (ICA), anti-glutamic aciddecarboxylase (GAD), anti-tyrosine phosphatase (IA-2) andanti-(pro)insulin (AIA) auto-antibodies, or the anti-carboxypeptidase H,anti-64 kD and anti-heat shock protein antibodies.

The type II prediabetic condition is characterised mainly by adisappearance of the early peak of insulin secretion, the consequence ofwhich is glucose intolerance (also known as IGT, for “impaired glucosetolerance”) or impaired fasting glycaemia (also known as IFG, for“impaired fasting glucose”).

No medicament exists for effectively preventing diabetes. It is thusdesirable to provide novel routes for the prevention and/or treatment ofprediabetes or diabetes. The main treatment of type I diabetes consistsof the subcutaneous injection of insulin. For type II diabetes, it islegitimate to propose a medicinal treatment when the level of glycatedhaemoglobin (A1c) remains higher than 7% after 3 to 6 months of the onlyhygieno-dietetic measurements. It is necessary to do this if the A1cremains higher than 8% (Nathan, N.E.J.M., (2002), 17: 1342-1349). TypeII diabetes is generally treated using oral active medicaments. Althoughmany oral antidiabetic agents are nowadays available, none of them makesit possible to achieve a normalisation of the glycaemic controlparameters. The diabetic complications associated with hyperglycaemiainevitably appear. The main weakness of these medicaments is that theyaddress only one defect at a time, either insulin resistance(thiazolidinediones or biguanides) or insulin secretion (sulfonylureas,glinides, etc.). Furthermore, no medicament capable of increasing thenumber and functionality of the islets of Langerhans cells is availableat the present time. Finally, some of them have non-negligible adverseeffects. Sulfonylureas in particular present a major risk ofhypoglycaemia, which demands that the dosage of these medicaments bescrupulously defined and complied with from patient to patient.Simultaneous correction of the two defects mentioned above without risksof associated hypoglycaemia would constitute a fundamental breakthroughin the treatment of type II diabetes and its complications. Theprevention of the associated cardiovascular risk, which represents oneof the major complications, would also be of important benefit todiabetic patients.

With the pancreatic and hepatic function as the central focus indiabetic pathology in the present invention, the Inventors focused on ametabolic pathway, namely the metabolism of tryptophan. Tryptophan is anamino acid whose involvement in controlling carbohydrate metabolism haspreviously been reported (Tsiolakis D. and V. Marks, Horm. Metabol.Res., 16 (1964), 226-229). Its complex metabolisation via kynurenineleads to the production of NAD+. Some of the intermediate metaboliteshave also been described as possibly being involved in glycaemia control(Connick J. and Stone, Medical hypothesis, 18 (1985), 371-376) and inparticular in the mechanisms for controlling the production of glucoseby the liver (“Effect of tryptophan and its metabolites on GNG inmammalian tissues”, Pogson et al., 1975) and/or in insulin secretion andsynthesis (Noto Y. and Okamoto, Acta Diabet. Lat., 15 (1978), 273-282;Rogers and Evangelista, Proc. Soc. Exp., 178 (1985), 275-278). Among theactive metabolites of this pathway are tryptophan itself, kynurenine andkynurenic acid. The concentration of these metabolites is controlled bythree enzymes: kynurenine 3-hydroxylase, kynureninase and kynurenineaminotransferase. Kynurenine aminotransferase has also been suspected ofbeing involved in the hypertension physiopathology of SHR rats(Spontaneously Hypertensive Rat; Kwok et al., JBC, 35779-35782,September 2002) which are otherwise insulin-resistant. Despite that, thejoint action of these metabolites on glucose production by the liver andon insulin secretion in response to glucose has not been demonstrated inthe prior art. In particular, it has not been demonstrated that some ofthese metabolites can restore a physiological response to glucose, thesecretion of the pancreatic hormones (insulin and glucagon), in animalsrendered diabetic by injection of streptozotocin, which would thus makeit possible to correct the insulin secretion defect without giving riseto any risk of hypoglycaemia.

It is well described in the prior art that certain metabolites of thekynurenine pathway, such as quinolinic acid and kynurenic acid, act asneurotoxic agents and neuroprotective agents, respectively, on thenervous system. These effects are linked to their capacity to modulateglutamate receptors and/or nicotinic receptors (Schwarcz R. andPellicciardi R., JPET 303 (2002), 1-10; Stone and Darlington, NatureReviews, 1 (2002), 609-620). The presence of glutamate receptors in thepancreas is described in the prior art, as is their involvement inpancreatic hormone secretion (Weaver C. et al., J. Biol. Chem., 271(1996), 12977-12984), but it has not been demonstrated that theseglutamate receptors are controlled by the kynurenine metabolites in thisorgan.

The research conducted with the aim of meeting the objectives of thepresent invention has made it possible to demonstrate, surprisingly,that the modulation of tryptophan metabolism in the kynurenine pathwayvia the pancreatic inhibition of kynurenine 3-hydroxylase allows anincrease in the number of islets of Langerhans cells and thus plays animportant role especially in the prevention and treatment of diabeticdiseases, its complications and/or its related pathologies (obesity,hypertension, etc.).

One of the objectives of the present invention consequently consists inproviding novel therapeutic means which have curative and/or preventiveactivity for the prevention of diabetes, its complications and/or itsrelated pathologies, by increasing the number of islets of Langerhanscells, and which are free of the risk of hypoglycaemia.

The present invention also proposes, as another objective, a process forthe treatment of diabetes that makes it possible to avoid the sideeffects and especially hypoglycaemia, the said process using therapeuticmeans whose mechanism of action for this type of pathology is notdescribed or suggested in the prior art.

Certain compounds are known (see patents U.S. Pat. No. 6,048,896 andU.S. Pat. No. 6,323,240), which have inhibitory activity on thekynurenine 3-hydroxylase and which are useful in the treatment ofneurodegenerative diseases, including diseases of the central nervoussystem, sclerosis and glaucoma-related retinopathy. Such compounds werealready known as having analgesic and anti-inflammatory properties.

The research conducted with the aim of meeting the objectives of thepresent invention has made it possible to demonstrate, surprisingly,that the inhibition of kynurenine 3-hydroxylase plays an important rolein the prevention and treatment of diabetic diseases, in particularnon-insulin-dependent diabetes, its complications and/or its relatedpathologies.

It has thus been discovered that compounds with inhibitory activity onkynurenine 3-hydroxylase increase the number of islets of Langerhanscells and are especially useful for the prevention and treatment ofdiabetes, its complications and/or its related pathologies.

The present inventors have now discovered, entirely unexpectedly, thatkynurenine 3-hydroxylase inhibitors show activity towards pancreaticbeta cells.

Specifically, according to the present invention, the kynurenine3-hydroxylase inhibitors increase the number of islets of Langerhanscells and in particular the beta cells.

The use of kynurenine 3-hydroxylase inhibitors should thus make itpossible to compensate for the reduction in the number of pancreaticislets of Langerhans cells in the course of the diabetic condition, inaddition to their effect on the function of these cells.

According to the invention, kynurenine 3-hydroxylase inhibitors thusmake it possible to prevent diabetes and its effects.

According to the invention, kynurenine 3-hydroxylase inhibitors thusmake it possible to specifically target the treatment of hyperglycaemiaas a function of the type of diabetes, its degree of progress and/or thepopulation concerned.

Also, the use of kynurenine 3-hydroxylase inhibitors makes it possibleto act selectively on the increase in the number of islets of Langerhanscells. This therefore makes it possible to selectively target patientswith an anomaly of insulin secretion of the islets of Langerhans cellsin response to glucose and/or an impairment in their number.

Specifically, the use of kynurenine 3-hydroxylase inhibitors makes itpossible to treat and/or prevent insulin-dependent diabetes, byincreasing the mass of insulin-secreting islets of Langerhans cells.

More particularly, kynurenine 3-hydroxylase inhibitors make it possibleto prevent insulin-dependent diabetes by increasing the number ofinsulin-secreting islets of Langerhans cells before the disease has beendeclared, more particularly during prediabetes.

Also, the use of kynurenine 3-hydroxylase inhibitors makes it possibleto treat and/or prevent early non-insulin-dependent diabetes, byincreasing the number of functional cells. This is particularlyadvantageous insofar as this use makes it possible to avoid increasingthe number of non-functional beta cells and reducing the mass of betacells, respectively, above or below the normal value, which thus makesit possible to advantageously avoid the appearance of diabetes, itssymptoms and/or its complications.

Also, the use of kynurenine 3-hydroxylase inhibitors makes it possibleto treat and/or prevent non-insulin-dependent diabetes at an advancedstage, known as a late stage, by replacing the non-functional beta cellswith functional beta cells.

Also, the use of kynurenine 3-hydroxylase inhibitors makes it possibleto treat and/or prevent late non-insulin-dependent diabetes byregenerating the number of beta cells, following the failure and/or areduction in the number of the beta cells.

According to the invention, the kynurenine 3-hydroxylase inhibitors maybe administered orally, in monotherapy, to prevent and/or treatnon-insulin-dependent diabetes.

According to the invention, the kynurenine 3-hydroxylase inhibitors canbe used in vitro for the treatment of pancreatic stem cells; the saidtreated cells may be transplanted into a patient to prevent and/or treatnon-insulin-dependent diabetes.

According to the invention, the kynurenine 3-hydroxylase inhibitors canbe used in vitro for the treatment of pancreatic stem cells; the saidtreated cells may be transplanted into a patient to prevent and/or treatinsulin-dependent diabetes.

According to the invention, the kynurenine 3-hydroxylase inhibitors maybe administered in combination with one or more agents for reducing thebody's immune response, to prevent and/or treat insulin-dependentdiabetes.

According to a first subject, the present invention thus relates to theuse of a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for increasing the number of islets of Langerhans cells.

According to a second subject, the present invention relates to the useof a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for the the treatment and/or prevention of insulin-dependentdiabetes.

According to another subject, the present invention relates to the useof a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for the prevention and/or treatment of insulin-dependentprediabetes.

According to another subject, the present invention relates to the useof a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for the prevention of non-insulin-dependent diabetes.

According to another subject, the present invention relates to the useof a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for the treatment of early non-insulin-dependent diabetes.

According to another subject, the present invention relates to the useof a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for the treatment of late non-insulin-dependent diabetes.

According to another subject, the present invention relates topharmaceutical compositions comprising a kynurenine 3-hydroxylaseinhibitor in combination with one or more immunosuppressants.

According to another subject, the present invention also relates to theuse of a kynurenine 3-hydroxylase inhibitor in combination with one ormore immunosuppressants, for the manufacture of a medicament for theprevention and/or treatment of insulin-dependent diabetes.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient with an impairment inthe number of islets of Langerhans cells. Preferably, the impairment inthe number of islets of Langerhans cells represents a decrease of atleast 40% in the number of cells, more preferably a decrease of between50% and 90%, and even more preferably between 60% and 85%.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient presenting anti-isletsof Langerhans cells immunological markers.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient presenting anydiabetic risk factor.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient with insulinresistance.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient presenting markers,such as glycated haemoglobin at concentrations higher than 7%.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient whose islets ofLangerhans cells show an anomaly of insulin secretion in response toglucose.

According to a preferred aspect, the present invention relates to any ofthe uses mentioned above in the case of a patient with relatedhyperglycaemia and obesity.

According to another aspect, the present invention relates to any of theuses mentioned above, comprising the in vitro treatment of isolatedislets of Langerhans cells with a kynurenine 3-hydroxylase inhibitor.

According to another subject, the present invention also relates to themethod for the in vitro treatment of isolated islets of Langerhans cellswith a kynurenine 3-hydroxylase inhibitor.

The culturing and transplantation of the said islets of Langerhans cellsmay especially be performed by application or adaptation of the methodsdescribed by Docherty et al., Current Opinion in Pharmacology.2001, 1:641-650.

According to the present invention, the term “prediabetes” means acondition characterised by one or more of the following factors: thepresence of anti-islets of Langerhans cells immunological markers, animpairment in the number of islets of Langerhans cells, suppression ofthe early peak of insulin secretion, glucose intolerance, an impairmenttin fasting glycaemia and/or any diabetic risk factor.

According to the invention, the expression “impairment in fastingglycaemia and/or glucose intolerance” means a fasting glycaemia ofbetween 1.10 g/l and 1.26 g/l and a glycaemia after meals of between1.40 g/l and 2 g/l after meals.

According to the invention, the expression “anti-islets of Langerhanscells immunological markers” means any immunological marker indicatingthe existence of an autoimmune response of the body directed against theantigenic markers of the body's islets of Langerhans cells. Thesemarkers include auto-antibodies, such as those described by Buysschaertet al., Louvain Med. 119, S251-S258, 2000. These antibodies are chosenfrom the anti-islet (ICA), anti-glutamic acid decarboxylase (GAD),anti-tyrosine phosphatase (IA-2) and anti-(pro)insulin (AIA)auto-antibodies, or the anti-carboxypeptidase H, anti-64 kD andanti-heat shock protein antibodies.

According to the invention, the expression “impairment in the number ofislets of Langerhans cells” means a decrease of at least 40% in thenumber of cells. Preferably, the impairment in the number of islets ofLangerhans cells represents a decrease of at least 40% in the number ofcells, more preferably a decrease of between 50% and 90% and even morepreferably between 60% and 85%.

According to the invention, the expression “anomaly of insulin secretionin response to glucose” means any impairment in the normal capacity ofthe islets of Langerhans cells to secrete insulin in response toglucose.

According to the invention, the expression “diabetic risk factor” meansany complaint directly or indirectly associated with the appearance ofdiabetes. These especially comprise familial history, gestationaldiabetes, excess weight, obesity, insufficient physical exercise, highblood pressure, a high level of triglycerides, inflammation,hyperlipidaemia, etc.

According to the invention, the term “immunosuppressant” means anyphysical agent (for example x-rays) chemical agent (for exampleazathioprine or mercaptopurine) or biological agent (for exampleanti-lymphocyte serum) for reducing or inhibiting the stimulation of animmune response of the body with an antigen.

According to the invention, the term “islets of Langerhans cells” meansthe alpha, beta, delta and PP cells mentioned above; more preferably,the islets of Langerhans cells represent the beta cells.

It has especially been discovered that the compounds corresponding tothe general formula (I) or to the general formula (II) describedhereinbelow generally have inhibitory activity on kynurenine3-hydroxylase. Among the compounds described in formulae (I) and (II),some families of compounds are known to have activity that is useful inthe treatment of diabetes, and especially the families of compoundscorresponding to patent application WO-A-98/07681 and the familiescorresponding to patent application EP-A-0 885 869. The compounds withsubstantial activity on kynurenine 3-hydroxylase are especiallypreferred. The term “substantial activity” means any inhibitory activityon the enzyme by the in vitro test process defined below, thus making itpossible to obtain an effective therapeutic action on the enzyme. Inparticular, an enzymatic activity of less than or equal to 70%,advantageously less than or equal to 50% and even more preferably lessthan or equal to 30% relative to the control, is preferred.

It has thus been discovered that, within these families of compounds, itis possible to use compounds that are characterised by inhibitoryactivity on kynurenine 3-hydroxylase to obtain an improved treatment orimproved medicaments, or for a different purpose, to increase the massof beta cells and especially to prevent or treat diabetes, and also thecomplications of this diabetes, via a novel route that offers unexpectedadvantages. They also make it possible to improve the prevention andtreatment of diabetes, especially of non-insulin-dependent diabetes, byadministration of a therapeutically effective amount to patients in needof inhibition of kynurenine 3-hydroxylase.

In particular, the compounds of family Ih are found to be noteworthykynurenine 3-hydroxylase inhibitors and agents for increasing the massof beta cells, especially antidiabetic agents.

Confirmation of the existence of inhibitory activity on kynurenine3-hydroxylase may be made by any known means and especially, in aparticularly simple manner, by subjecting the compound to an in vitrotest that will be defined hereinbelow.

More specifically, the compounds with inhibitory activity on kynurenine3-hydroxylase belong to the general formula (I) or to the generalformula (II) below:

in which:

W represents a divalent radical chosen from the following radicals:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl,alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl and aheterocyclic radical;

R² and R³ together also possibly forming a group ═CR¹⁶R¹⁷; oralternatively together forming, with the carbon atom that bears them, acycloalkyl radical or a heterocyclic radical;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)), —N(R¹²)OR¹³, linear or branched alkylcontaining from 1 to 14 carbon atoms and optionally substituted,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and aheterocyclic radical;

R⁵, R⁶, R⁷ and R⁸, which may be identical or different, are chosen,independently of each other, from hydrogen, a halogen atom, and a nitro,cyano, hydroxyl, trifluoromethyl, alkyl, alkoxy, cycloalkyl or arylradical;

the radicals R⁵ and R⁶, on the one hand, or R⁶ and R⁷, on the otherhand, may also form, together with the carbon atoms to which they areattached, a benzene ring optionally substituted by one or more groups,which may be identical or different, chosen from a halogen atom, atrifluoromethyl, cyano or nitro radical, an alkyl radical and an alkoxyradical;

R⁹ represents hydrogen organ alkyl radical;

R¹⁰ is chosen from an alkyl, an aryl and a heteroaryl radical;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl,alkoxycarbonyl, aryl, arylalkyl, heteroaryl, cycloalkyl and aheterocyclic radical; R¹⁴ may also form a bond with R², thus forming adouble bond between the carbon atoms respectively bearing thesubstituents R¹⁴ and R²; or alternatively R¹⁴ forms, with R² and withthe carbon atoms that bear them, a ring containing a total of 3, 4, 5, 6or 7 carbon atoms, among which 1, 2 or 3 may be replaced with an atomchosen from nitrogen, oxygen and sulfur, the said ring possiblycomprising one or more unsaturations in the form of (a) double bond(s),and being optionally substituted by one or more radicals, which may beidentical or different, chosen from oxo, alkoxy, alkoxycarbonyl andalkylcarbonyloxy;

R¹⁵ is chosen from hydrogen a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkoxy,alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy,heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio,cycloalkylthio, heteroarylthio, heterocyclylthio, aryl, heteroaryl,cycloalkyl and a heterocyclic radical;

R¹⁴ and R¹⁵ also possibly forming, together with the carbon atom thatbears them, a cycloalkyl radical or a heterocyclic radical;

R¹⁶ and R¹⁷, which may be identical or different, are chosen,independently of each other, from hydrogen, a halogen atom, an alkyl,aryl, heteroaryl or cycloalkyl radical and a heterocyclic radical; oralternatively

R¹⁶ and R¹⁷ form, together with the carbon atom that bears them, acycloalkyl radical or a heterocyclic radical; and

R¹¹ is chosen from hydrogen and an alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl radical, and anyprotecting group for is an amine function;

and also the possible geometrical and/or optical isomers thereof, andpossible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

The following definitions specify the natures of the various groups andradicals defined above. Unless otherwise indicated, these definitionsapply for all the terms of the present invention thus explained.

The term “halogen atom” denotes a fluorine, chlorine, bromine or iodineatom.

The term “alkyl” denotes a linear or branched alkyl radical containingfrom 1 to 6 carbon atoms, optionally substituted by one or more chemicalgroups chosen from hydroxyl, carboxyl, cyano, nitro, —N(R¹²R^(12′)),—N(R¹²)OR¹³, aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl,alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom,trifluoromethyl, thiol, —SR^(13′), —S(O)R^(13′) and —S(O₂)R^(13′), withR^(13′) having the same definition as R¹³, with the exception ofhydrogen. The possible substituents on the alkyl radical containing from1 to 14 carbon atoms may be identical to those described above.

The term “alkenyl” denotes an alkenyl radical containing one or moredouble bonds; the said radical, which is linear or branched, and whichcontains from 2 to 6 carbon atoms, is optionally substituted by one ormore chemical groups chosen from hydroxyl, carboxyl, cyano, nitro,—N(R¹²R^(12′)), —N(R¹²)OR¹³, aryl, heteroaryl, cycloalkyl, heterocyclicradical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl,halogen atom, trifluoromethyl, thiol, —SR^(13′), —S(O)R^(13′) and—S(O₂)R^(13′), with R^(13′) having the same definition as R¹³, with theexception of hydrogen.

The term “alkynyl” denotes an alkynyl radical containing one or moretriple bonds; the said radical, which is linear or branched, and whichcontains from 2 to 6 carbon atoms, is optionally substituted by one ormore chemical groups chosen from hydroxyl, carboxyl, cyano, nitro,—N(R¹²R^(12′)), —N(R¹²)OR¹³, aryl, heteroaryl, cycloalkyl, heterocyclicradical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl,halogen atom, trifluoromethyl, thiol, —SR^(13′), —S(O)R^(13′) and—S(O₂)R^(13′), with R^(13′) having the same definition as R¹³, with theexception of hydrogen.

The term “alkoxy” should be understood as being “alkyl”+“oxy”, in whichthe term “alkyl” is as defined above. The substituents of the alkoxyradical are identical to those defined for the alkyl radical.

The term “cycloalkyl” denotes a bridged or non-bridged monocyclic,bicyclic or tricyclic cycloalkyl radical containing from 3 to 13 carbonatoms, optionally substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, carboxyl, cyano, nitro,—N(R¹²R^(12′)), —N(R¹²)OR¹³, aryl, heteroaryl, cycloalkyl, heterocyclicradical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl,halogen atom, trifluoromethyl, thiol, —SR^(13′), —S(O)R^(13′) and—S(O₂)R^(13′), with R^(13′) having the same definition as R¹³, with theexception of hydrogen.

The term “cycloalkenyl” denotes a cycloalkyl radical as defined abovecomprising at least one double bond.

The term “heterocyclic radical” or “heterocyclyl” denotes a monocyclicor bicyclic radical containing a total of 5 to 10 atoms, among which 1,2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygenand sulfur, the said heterocyclic radical also optionally comprising 1,2, 3 or 4 double bonds and being optionally substituted by one or morechemical groups, which may be identical or different, chosen fromhydroxyl, carboxyl, cyano, nitro, —N(R¹²R^(12′)), —N(R¹²)OR¹³, aryl,heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl,alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl,thiol, —SR^(13′), —S(O)R^(13′) and —S(O₂)R^(13′), with R^(13′) havingthe same definition as R³, with the exception of hydrogen.

The term “aryl” denotes a monocyclic, bicyclic or tricyclic aryl radicalcontaining from 6 to 14 carbon atoms, optionally substituted by one ormore chemical groups, which may be identical or different, chosen fromhydroxyl, carboxyl, cyano, nitro, —N(R¹²R^(12′)) —N(R¹²)OR¹³; aryl,heteroaryl, cycloalkyl; heterocyclic: radical, alkyl, alkenyl, alkynyl,alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl,thiol, —SR^(13′), —S(O)R^(13′) and —S(O₂)R^(13′), with R^(13′) havingthe same definition as R¹³, with the exception of hydrogen.

The term “heteroaryl” denotes a monocyclic or bicyclic heteroarylradical containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4are chosen, independently of each other, from nitrogen, oxygen andsulfur, the said heteroaryl radical being optionally substituted by oneor more chemical groups, which may be identical or different, chosenfrom hydroxyl, carboxyl, cyano, nitro, —N(R¹²R^(12′)), —N(R¹²)OR¹³,aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl,alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom,trifluoromethyl, thiol, —SR^(13′), —S(O)R^(13′) and —S(O₂)R^(13′), withR^(13′) having the same definition as R¹³, with the exception ofhydrogen.

A preferred aryl radical is the phenyl radical or the 1-naphthyl,2-naphthyl or fluorenyl radical.

Among the alkyl and alkoxy radicals substituted by an aryl radical, thebenzyl, benzyloxy, phenethyl, phenylethoxy, naphthylmethyl andnaphthylmethoxy radicals are particularly preferred.

Among the cycloalkyl radicals that are preferred are cyclopropyl,cyclopentyl, cyclohexyl, the adamantyl radical and radicals derived fromtetralin and from decalin.

The terms “heteroaryl radical” and “heterocyclic radical” preferablymean a pyridyl, furyl, thienyl, 1-quinolyl, 2-quinolyl, tetrahydrofuryl,tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl,pyranyl, thiopyranyl, indanyl, benzothienyl or benzofuryl radical.

For the compounds of the formulae (I) and (II) presented above, the term“geometrical isomer” means a cis/trans or E/Z isomerism. Moreparticularly, for the compounds of the formula (I) and when R¹⁴ forms abond with R², thus forming a double bond between the carbon atomsrespectively bearing the substituents R¹⁴ and R², this double bond maybe of E or Z configuration. These geometrical isomers, which may or maynot be pure, alone or as a mixture, form an integral part of thecompounds of the formula (I).

The term “optical isomer” includes all the forms of isomers, alone or asmixtures, arising from the presence of one or more axes and/or centresof symmetry in the molecule, and resulting in the rotation of a beam ofpolarised light. The term “optical isomer” more particularly includesthe enantiomers and diastereoisomers, in pure form or as a mixture.

In particular, for the compounds of the formula (I), and when thesubstituents R² and R³, on the one hand, and/or the substituents R¹⁶ andR¹⁷, on the other hand, are different, the carbon atoms bearing thesepairs of substituents are asymmetric, and thus lead to enantiomersand/or diastereoisomers. These optical isomers, which may or may not bepure, alone or as a mixture, form an integral part of the compounds ofthe formula (I).

Among the acids capable of forming pharmaceutically acceptable saltswith the compounds of the formula (I) or of the formula (II) above,non-limiting examples that may be mentioned include hydrochloric acid,phosphoric acid, sulfuric acid, tartaric acid, citric acid, maleic acid,acetic acid, fumaric acid, alkylsulfonic acid and camphoric acid.

Among the bases capable of forming pharmaceutically acceptable saltswith the compounds of the formula (I) or of the formula (II) above,non-limiting examples that may be mentioned include sodium hydroxide,potassium hydroxide, diethylamine, triethylamine, ethanolamine,diethanolamine, arginine and lysine.

The compounds of the formulae (I) and (II) above also comprise theprodrugs of these compounds.

The term “prodrugs” means compounds which, once administered to thepatient, are chemically and/or biologically transformed by the livingbody, into compounds of the formula (I) or (II).

Examples of prodrugs of compounds of the formula (I) above are those forwhich R⁴ represents a radical —OP, in which P is a leaving group, forexample a sugar residue, such as sucrose, which can thus lead tocompounds in which R⁴ represents —OH. Such prodrugs are included in thefield of the present invention.

A large number of compounds of the formulae (I) and (II) defined aboveare known, especially by the patent publications and patent applicationsU.S. Pat. No. 6,048,896, U.S. Pat. No. 6,323,240, EP 0 885 869 and U.S.Pat No. 5,877,193. These publications provide the processes for thepreparation of these various compounds, to which processes a personskilled in the art may refer, or may adapt, to synthesise all thecompounds of the formulae (I) and (II).

According to one variant of the present invention, the compounds of theformula (I) that are preferred are those having the followingcharacteristics, taken separately or in combination:

W represents a divalent radical chosen from the following radicals:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl andaryl;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl,alkenyl, alkoxy, alkylthio and aryl;

R² and R³ together also possibly forming a group ═CR¹⁶R¹⁷;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)), —N(R¹²)OR¹³, linear or branched alkylcontaining from 1 to 14 carbon atoms and optionally substituted,cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;

R¹² and R^(12′), which may be identical or different, are chosen, isindependently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,—N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryland arylalkyl; R¹⁴ may also form a bond with R², thus forming a doublebond between the carbon atoms respectively bearing the substituents R¹⁴and R²; or alternatively R¹⁴ forms, with R² and with the carbon atomsthat bear them, a ring containing a total of 3, 4, 5 or 6 carbon atoms,among which 1, 2 or 3 may be replaced with an atom chosen from nitrogenand oxygen, the said ring possibly comprising one or more unsaturationsin the form of (a) double bond(s), and being optionally substituted byone or more radicals, which may be identical or different, chosen fromoxo, alkoxy, alkoxycarbonyl and alkylcarbonyloxy;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkylcarbonyl, alkoxycarbonyl, alkoxy, alkylthio andaryl;

R¹⁶ is chosen from hydrogen and an alkyl or aryl radical;

R¹⁷ represents a hydrogen atom; and

R¹¹ is chosen from hydrogen and any protecting group for an aminefunction;

and also the possible geometrical and/or optical isomers thereof, andpossible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and the possible salts thereof with a pharmaceutically acceptable acidor base, or alternatively the pharmaceutically acceptable prodrugs ofthese compounds.

According to another variant of the present invention, this inventionrelates to the use of compounds of the, formula (Ia) that haveinhibitory activity on kynurenine 3-hydroxylase, for the preparation ofa medicament for the prevention and/or treatment of diabetes. Thesecompounds of the formula (Ia) have the general structure (I) as definedabove, in which:

W represents a divalent radical chosen from the following radicals:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl,alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl and aheterocyclic radical;

R² and R³ together also possibly forming a group ═CR¹⁶R¹⁷, oralternatively forming, together with the carbon atom that bears them, acycloalkyl radical or a heterocyclic radical;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)), —N(R¹²)OR¹³, linear or branched alkylcontaining from 1 to 14 carbon atoms and optionally substituted,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and aheterocyclic radical;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl,alkoxycarbonyl, aryl, arylalkyl, heteroaryl, cycloalkyl and aheterocyclic radical; R¹⁴ may also form a bond with R², thus forming adouble bond between the carbon atoms respectively bearing thesubstituents R¹⁴ and R²; or alternatively R¹⁴ forms, with R² and withthe carbon atoms that bear them, a ring containing a total of 3, 4, 5, 6or 7 carbon atoms, among which 1, 2 or 3 may be replaced with an atomchosen from nitrogen, oxygen and sulfur, the said ring possiblycomprising one or more unsaturations in the form of (a) double bond(s),and being optionally substituted by one or more radicals, which may beidentical or different, chosen from oxo, alkoxy, alkoxycarbonyl andalkylcarbonyloxy;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl,alkyl, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkoxy,alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy,heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio,cycloalkylthio, heteroarylthio, heterocyclylthio, aryl, heteroaryl,cycloalkyl and a heterocyclic radical;

R¹⁴ and R¹⁵ also possibly forming, together with the carbon atom thatbears them, a cycloalkyl radical or a heterocyclic radical;

R¹⁶ and R¹⁷, which may be identical or different, are chosen,independently of each other, from hydrogen, a halogen atom, an alkyl,aryl, heteroaryl or cycloalkyl radical and a heterocyclic radical; oralternatively R¹⁶ and R¹⁷ form, together with the carbon atom that bearsthem, a cycloalkyl radical or a heterocyclic radical; and

R¹¹ is chosen from hydrogen and an alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl radical, and anyprotecting group for an amine function;

with the restriction that when R³, R² and R¹⁴ each represent hydrogen,then R¹⁵ is other than an alkyl radical, optionally substituted by aryl,heteroaryl, cycloalkyl and a heterocyclic radical;

and also the possible geometrical and/or optical isomers thereof, andpossible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and the possible salts thereof with a pharmaceutically acceptable acidor base, or alternatively the pharmaceutically acceptable prodrugs ofthese compounds.

Among the compounds (Ia) defined above, the compounds that will also bepreferred are those of the family (Ib) belonging to formula (I) inwhich:

W represents a divalent radical chosen from the radicals:

R¹ represents a phenyl radical, optionally substituted by 1, 2 or 3groups chosen from cyano, nitro, phenyl, benzyl, alkyl, alkenylcontaining from 2 to 4 carbon atoms, alkynyl containing from 2 to 4carbon atoms, alkoxy, thiol —SR^(13′), —S(O)R^(13′) and —S(O₂)R^(13′),and a halogen atom;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionallysubstituted alkyl, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkoxy, alkylthio and phenyl;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionallysubstituted alkyl, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkoxy, alkylthio and phenyl;

R² and R³ together also possibly forming a group ═CR¹⁶R¹⁷;

R⁴ is chosen from hydroxyl, optionally substituted alkoxy, in particularbenzyloxy, alkenyloxy containing from 2 to 4 carbon atoms, alkynyloxycontaining from 2 to 4 carbon atoms, phenoxy, —N(R¹²R^(12′)) and—N(R¹²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen, an optionally substitutedalkyl radical, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkynyl containing from 2 to 4 carbon atoms, and phenyl;

R¹³ is chosen from hydrogen, an optionally substituted alkyl radical, inparticular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkynylcontaining from 2 to 4 carbon atoms, and phenyl;

R13′ is chosen from an optionally substituted alkyl radical, inparticular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkynylcontaining from 2 to 4 carbon atoms, phenyl and —N(R¹²R^(12′));

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionallysubstituted alkyl, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkoxy, alkylthio and phenyl; R¹⁴ may also form a bondwith R², thus forming a double bond between the carbon atomsrespectively bearing the substituents R¹⁴ and R²;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionallysubstituted alkyl, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkoxy, alkylthio and phenyl;

R¹⁶ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionallysubstituted alkyl, in particular benzyl, alkenyl containing from 2 to 4carbon atoms, alkoxy, alkylthio and phenyl; and

R¹⁷ represents a hydrogen atom;

with the restriction that when R³, R² and R¹⁴ each represent hydrogen,then R¹⁵ is other than an alkyl radical, optionally substituted by aryl,heteroaryl, cycloalkyl and a heterocyclic radical;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

In the vast majority, the compounds (Ib) defined above show entirelyadvantageous inhibitory activity on kynurenine 3-hydroxylase. As aresult, these compounds are most particularly preferred and simple touse for any of the abovementioned uses according to the invention.

According to another variant of the invention, this invention relates tothe use of compounds of the family (Ic) as kynurenine 3-hydroxylaseinhibitors in any of the abovementioned uses according to the invention.These compounds of family (Ic) have the general structure (I) as definedabove, in which:

W represents the divalent radical:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)) and —N(R¹²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen;

R¹⁵ represents hydrogen;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

According to another variant, the invention relates to the use ofcompounds of the family (Id) as kynurenine 3-hydroxylase inhibitors inany of the above-mentioned uses according to the invention, the saidcompounds (Id) having the general structure (I) as defined above, inwhich:

W represents the divalent radical:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)) and —N(R¹²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen; and

R¹⁵ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,cycloalkyloxy, heteroaryloxy and heterocyclyloxy;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

Another preferred group of compounds consists of the compounds of family(Ie) as kynurenine 3-hydroxylase inhibitors in any of the abovementioneduses according to the invention, the said compounds (Ie) belonging tothe general formula (I) as defined above, in which:

W represents the divalent radical:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² and R¹⁴ together form a bond, thus forming a double bond between thecarbon atoms respectively bearing R² and R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)) and —N(R¹²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical; and

R¹⁵ represents hydrogen;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

According to another variant of the present invention, this inventionrelates to the use of compounds of family (If) as kynurenine3-hydroxylase inhibitors in any of the abovementioned uses according tothe invention, the said compounds (If) belonging to the general formula(I) as defined above, in which:

W represents the divalent radical:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical;

R² and R¹⁴ together form a bond, thus forming a double bond between thecarbon atoms respectively bearing R² and R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R²R²′) and —N(R²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical; and

R¹⁵ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,cycloalkyloxy, heteroaryloxy and heterocyclyloxy;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compound.

Among the compounds of the general formula (I), and according to anothervariant of the invention, the compounds are chosen from the family ofcompounds (Ig) consisting of:

-   4-(4′-methylcyclohexyl)-4-oxobutanoic acid;-   2-hydroxy-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   2-methoxy-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   2-hydroxy-3-methyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-hydroxy-3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-hydroxy-3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-methyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-methyl-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   2-chloro-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-chloro-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   2-fluoro-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-fluoro-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   2-thiomethyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-methylidene-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-phenyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   3-methyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   methyl (R,S)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoate;-   methyl (R,S)-2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoate;-   4-(3′-fluorophenyl)-4-oxo-2-butenoic acid;-   4-(3′-chlorophenyl)-4-oxo-2-butenoic acid;-   4-(3′-nitrophenyl)-4-oxo-2-butenoic acid;-   4-(3′-fluoro-4′-methoxyphenyl)-4-oxo-2-butenoic acid;-   2-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   3-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   2,3-dimethyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   2-hydroxy-4-(3′-chlorophenyl)-4-oxo-2-butenoic acid;-   2-hydroxy-4-(3′-fluorophenyl)-4-oxo-2-butenoic acid;-   2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   2-hydroxy-4-(3′,4′-difluorophenyl)-4-oxo-2-butenoic acid; and-   2-hydroxy-4-(3′-chloro-4′-methoxyphenyl)-4-oxo-2-butenoic acid;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

According to another variant of the invention, a family of compounds(Ih) having the abovementioned general structure (I) is defined, forwhich:

W represents the divalent radical:

R¹, R², R³, R¹², R^(12′); R¹³ and R¹⁴ areas defined above; and

R¹⁵ is chosen from a thiol, alkylthio, alkenylthio, alkynylthio,arylthio, cycloalkylthio, heteroarylthio or heterocyclylthio radical;

with the restriction that when R², R³ and R¹⁴ each represent hydrogen,then R¹⁵ cannot represent a thiol or alkylthio radical;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

The compounds of family (Ih) form a particularly preferred aspect of thepresent invention. The compounds of family (Ih) have entirely noteworthyhypoglycaemiant properties and, in this respect, are useful askynurenine 3-hydroxylase inhibitors in any of the abovementioned usesaccording to the invention.

In addition, the compounds of family (Ih) show inhibitory activity onkynurenine 3-hydroxylase that may be linked to the observed effect onthe increase in the mass of beta cells, especially in the case ofdiabetes.

A preferred subfamily of the compounds of the family (Ih) consists ofthe compounds of the family (Ii) belonging to the general formula (I) inwhich:

W represents the divalent radical:

R¹ represents an aryl radical;

R² represent hydrogen, or forms a bond with R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,heteroaryloxy, —N(R¹²R^(12′)) and —N(R¹²)OR¹³;

R¹² and R^(12′), which may be identical or different, are chosen,independently of each other, from hydrogen and an alkyl, alkenyl,alkynyl, alkylcarbonyl, aryl or heteroaryl radical; or alternatively R¹²and R^(12′) may form, together with the nitrogen atom to which they areattached, a monocyclic or bicyclic heterocyclic group containing a totalof 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently ofeach other, from nitrogen, oxygen and sulfur, the said heterocyclicradical also optionally comprising 1, 2, 3 or 4 double bonds andoptionally being substituted by one or more chemical groups, which maybe identical or different, chosen from hydroxyl, halogen atom, alkyl,alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclicradical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl,heteroaryl, —N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen, or forms a bond with R²; and

R¹⁵ represents an arylthio radical;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

Among the compounds of family (Ii) that are also preferred are thecompounds of family (Ij) corresponding to the general formula (I), inwhich:

W represents the divalent radical:

R¹ represents a phenyl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl and an alkoxy radical;

R¹⁴ represents hydrogen; and

R¹⁵ represents a phenylthio radical;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

By way of illustration, examples of compounds of family (Ih) are:

compound Ih-1:

-   2-(2′-naphthylthio)-4-phenyl-4-oxobutanoic acid;

compound Ih-2:

-   2-phenylthio-4-phenyl-4-oxobutanoic acid;

compound Ih-3:

-   2-(4′-fluorophenylthio)-4-phenyl-4-oxobutanoic acid;

compound Ih-4:

-   2-(4′-chlorophenylthio)-4-phenyl-4-oxobutanoic acid;

compound Ih-5:

-   2-(4′-methylphenylthio)-4-phenyl-4-oxobutanoic acid;

compound Ih-6:

-   2-(4′-methoxyphenylthio)-4-phenyl-4-oxobutanoic acid;

compound Ih-7:

-   2-cyclohexylthio-4-phenyl-4-oxobutanoic acid;

compound Ih-8:

-   2-benzylthio-4-phenyl-4-oxobutanoic acid;

compound Ih-9:

-   ethyl 2-phenylthio-4-phenyl-4-oxobutanoate;

compound Ih-10:

-   ethyl 2-(4′-fluorophenylthio)-4-phenyl-4-oxobutanoate;

compound Ih-11:

-   ethyl 2-(4′-chlorophenylthio)-4-phenyl-4-oxobutanoate;

compound Ih-12:

-   ethyl 2-(4′-methylphenylthio)-4-phenyl-4-oxobutanoate;

compound Ih-13:

-   ethyl 2-(4′-methoxyphenylthio)-4-phenyl-4-oxobutanoate;

compound Ih-14:

-   ethyl 2-(2′-naphthylthio)-4-phenyl-4-oxobutanoate;

compound Ih-15:

-   ethyl 2-cyclohexylthio-4-phenyl-4-oxobutanoate;

compound Ih-16:

-   ethyl 2-benzylthio-4-phenyl-4-oxobutanoate;

compound Ih-17:

-   2-phenylthio-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-18:

-   2-(4′-fluorophenylthio)-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-19:

-   2-(4′-chlorophenylthio)-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-20:

-   2-(4′-methylphenylthio)-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-21:

-   2-(4′-methoxyphenylthio)-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-22:

-   2-(2′-naphthylthio)-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-23:

-   2-cyclohexylthio-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-24:

-   2-benzylthio-4-(4′-methoxyphenyl)-4-oxobutanoic acid;

compound Ih-25:

-   2-phenylthio-4-(4′-chlorophenyl)-4-oxobutanoic acid;

compound Ih-26:

-   2-(4′-fluorophenylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;

compound Ih-27:

-   2-(4′-chlorophenyl)-4-(4′-chlorophenyl)-4-oxobutanoic acid;

compound Ih-28:

-   2-(4′-methylphenylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;

compound Ih-29:

-   2-(4′-methoxyphenylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;

compound Ih-30:

-   2-(2′-naphthylthio)-4-(4′-chlorophenyl)-4-oxobutanoic acid;

and 2-carboxymethylthio-4-phenyl-4-oxobutanoic acid (f);

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically,acceptable prodrugsof these compounds.

It has been discovered, unexpectedly, that the compounds of the formula(I) according to the variants described above show particularlyadvantageous activity when R¹ is aryl or heteroaryl; these groups arethus most particularly preferred.

According to one particular aspect of the invention, among the differentvariants of the formula (I) above that are preferred are the compoundsfor which, when R²═R³═H, W is other than —CH(CH₂—X)— in which X=alkyl,aryl, cycloalkyl, pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl,tetrahydrofuryl, tetrahydropyranyl, piperidyl or pyrrolidinyl, which areoptionally substituted.

According to another particular aspect of the invention, the compoundsof the formula (I) are different from:

-   racemic 2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid and the R    and S isomers thereof;-   racemic 2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid and the R and    S isomers thereof;-   2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid;-   2-benzyl-4-phenyl-4-oxobutanoic acid;-   2-(β-naphthylmethyl)-4-phenyl-4-oxobutanoic acid;-   2-benzyl-4-(β-naphthyl)-4-oxobutanoic acid;-   2-[(4-chlorophenyl)methyl]-4-(4-methoxyphenyl)-4-oxobutanoic acid;-   2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid;-   4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxobutanoic acid;-   2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid;-   2-benzyl-4-cyclohexyl-4-oxobutanoic acid;-   4-phenyl-2-[(tetrahydrofur-2-yl)methyl]-4-oxobutanoic acid.

Among the compounds of the formula (II) defined above that are preferredare the compounds of the family (IIa) corresponding to the generalformula (II) in which:

R⁵, R⁶, R⁷ and R⁸ are as defined above;

R⁹ represents hydrogen; and

R¹⁰ is chosen from a phenyl radical, optionally substituted in position3 and/or 4 with an alkyl or alkoxy radical, preferably methyl ormethoxy, and a naphthyl radical;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

Another family (IIb) of compounds of the formula (II) is represented bythe compounds of the general formula (II) in which:

R⁵, R⁶, R⁷ and R⁸, which may be identical or different, are chosen,independently of each other, from hydrogen, a halogen atom, a nitroradical and a trifluoromethyl radical;

the radicals R⁶ and R⁷ also possibly forming, together with the carbonatoms to which they are attached, a benzene ring, optionally substitutedby one or more groups, which may be identical or different, chosen froma halogen atom and a trifluoromethyl, nitro or alkoxy radical; and

R⁹ and R¹⁰ are as defined above;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

According to one preferred variant of the invention, the compounds ofthe formula (II) are chosen from the list consisting of:

-   4-methoxy-N-(4-naphthalen-2-ylthiazol-2-yl)benzenesulfonamide;-   4-amino-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   4-methyl-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   4-methoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   2-naphthalenesulfonic    acid[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide;-   N-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide;-   4-methyl-N-[4-(4-nitrophenyl)thiazol-2-yl]benzenesulfonamide;-   4-amino-N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide;    and-   3,4-dimethoxy-N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]benzenesulfenamide;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

Among the variants of the formulae (I) and (II) described above, thecompounds that are preferred according to the invention are those withsubstantial inhibitory activity on kynurenine 3-hydroxylase as definedabove.

The compounds of the formulae (I) and (II) defined above are useful askynurenine 3-hydroxylase inhibitors for any of the uses according to theinvention defined above.

The pharmaceutical uses or compositions according to the invention thuscomprise as active principle a pharmacologically effective amount of atleast one kynurenine 3-hydroxylase inhibitor, preferably a compound ofthe formula (I) or of the formula (II), alone or in combination with oneor more fillers, vehicles, colorants or sweeteners, i.e. any suitableand pharmaceutically acceptable non-toxic, inert excipient usually usedin the production of pharmaceutical compositions.

The said compositions are administered to patients in need thereof, i.e.to individuals whose condition might be prevented or improved byincreasing the number of islets of Langerhans cells.

According to the invention, the kynurenine 3-hydroxylase inhibitors maybe useful in combination with an active agent usually used in thetreatment of diabetes, as a main active principle or as an adjuvantand/or potentiator of the said agent.

The pharmaceutical compositions thus obtained will be in various forms,the most advantageous being gel capsules, suppositories, injectable ordrinkable solutions, patches, plain, sugar-coated, film-coated orsublingual tablets, sachets, packets, lozenges, creams, ointments,dermal gels, aerosols, etc.

The working dose may be adapted according to the nature and severity ofthe pathology to be treated, the administration route and also thepatient's age and weight. In general, the unit dose will range between 5mg and 2000 mg per day, in one or more dosage intakes, advantageouslybetween 10 mg and 1000 mg, for example between 50 mg and 800 mg.

It has been discovered, surprisingly, that the kynurenine 3-hydroxylaseinhibitors have the twofold activity of controlling the secretion ofboth glucagon and insulin. Specifically, in the absence of glucose, thesecretion of glucagon is stimulated whereas that of insulin is not. Inthe presence of glucose, the secretion of insulin is potentiated whereasthe secretion of glucagon remains normally inhibited.

Such a dual activity affords a considerable improvement over theprocesses for the treatment of diabetes currently used. Specifically,the risks of hypoglycaemia are very greatly reduced, or even virtuallynonexistent, even when the prescribed doses and/or number ofadministrations are exceeded or have been poorly controlled.

The abovementioned uses according to the invention thus make it possibleto minimise or eliminate the risk of hypoglycaemia.

Among the compounds of the formula (I) that have inhibitory activity onkynurenine 3-hydroxylase, non-limiting examples that may be mentionedinclude:

-   4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   methyl 4-(3′,4′-dichlorophenyl)-4-oxobutanoate;-   (R,S)-2-hydroxy-4-(3′-chlorophenyl)-4-oxobutanoic acid;-   (R,S)-2-hydroxy-4-(3′-fluorophenyl)-4-oxobutanoic acid;-   (R,S)-2-hydroxy-4-(3′-nitrophenyl)-4-oxobutanoic acid;-   (R,S)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (S)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   methyl (R,S)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoate;-   (R,S)-2-hydroxy-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   (R,S)-2-methoxy-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   (R,S)-2-methoxy-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-2-methyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-3-methyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   2-hydroxy-3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-2-methyl-4-(3′,4′-difluorophenyl)-4-oxobutanoic acid;-   (R,S)-2-chloro-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-2-methylidene-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-3-phenyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   methyl (R,S)-2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoate;-   (R,S)-2-phenyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (R,S)-2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid;-   (E)-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   (E)-4-(3′,4′-difluorophenyl)-4-oxo-2-butenoic acid;-   (E)-4-(3′-fluorophenyl)-4-oxo-2-butenoic acid;-   (E)-4-(3′-chlorophenyl)-4-oxo-2-butenoic acid;-   (E)-4-(3′-nitrophenyl)-4-oxo-2-butenoic acid;-   (E)-2-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   3-methyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   3-benzyl-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   (E)-2-hydroxy-4-(3′-chlorophenyl)-4-oxo-2-butenoic acid;-   (E)-2-hydroxy-4-(3′-fluorophenyl)-4-oxo-2-butenoic acid;-   (E)-2-hydroxy-4-(4′-chlorophenyl)-4-oxo-2-butenoic acid;-   (E)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoic acid;-   (E)-2-hydroxy-4-(3′,4′-difluorophenyl)-4-oxo-2-butenoic acid;-   methyl (E)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoate; and-   ethyl (E)-2-hydroxy-4-(3′,4′-dichlorophenyl)-4-oxo-2-butenoate;

and also the possible geometrical and/or optical isomers thereof, andthe possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptableacid or base, or alternatively the pharmaceutically acceptable prodrugsof these compounds.

The invention also relates to a process for increasing the number ofislets of Langerhans cells, comprising the administration, to a patientrequiring it, of a dose of one or more compounds that inhibit kynurenine3-hydroxylase of the formula (I) or of the formula (II) defined above,such that it produces a substantial inhibition of kynurenine3-hydroxylase in the patient.

In particular, the process defined above allows the prevention ortreatment of diabetes and/or its complications, especially in the caseof patients presenting the characteristics of the diabetes pathology,without this pathology yet having been declared. The criteria fordiagnosing this pathology are defined, for example, in Diabetes Care,vol. 25, suppl. 1, January 2002.

Among the complications that may be mentioned especially are arterialhypertension, diabetes-related inflammatory processes, diabeticnephropathy, macroangiopathy and microangiopathy, peripheral diabeticneuropathy and retinopathy of diabetic origin.

As mentioned previously, the compounds of the formulae (I) and (II)defined above have been found to be useful in the prevention and/ortreatment of diabetes and its complications, by increasing the number ofislets of Langerhans cells, according to a mode of action that ishitherto unknown in this therapeutic field.

The invention also relates to a process for manufacturing medicamentsfor increasing the number of islets of Langerhans cells, especially forthe the treatment and/or prevention of diabetes and its complications,by inhibiting kynurenine 3-hydroxylase, in which at least one compoundof the formula (I) or (II) is subjected to an in vitro test ofinhibition of kynurenine 3-hydroxylase, and the molecules respondingpositively to the said tests are then conditioned in the form of apharmaceutical composition, optionally with addition of apharmaceutically acceptable filler or vehicle.

Finally, the invention also relates to a process for screening candidatecompounds for activity in increasing the number of islets of Langerhanscells, especially for the the treatment and/or prevention of diabetes orits complications, by inhibiting kynurenine 3-hydroxylase, the saidcandidates not corresponding to formula (I) or (II), in which processthe candidate compounds are subjected to an in vitro test of inhibitionof kynurenine 3-hydroxylase, and the candidate that has respondedpositively to this test is selected.

Among the candidates that will be preferred are the compounds alreadyknown as having antidiabetic activity.

The examples that follow illustrate, without placing any limitation ofany kind on the invention, some of the subjects of the invention, inparticular the preparation processes and the activities of some of thecompounds described above in antidiabetic activity tests and tests ofinhibition of kynurenine 3-hydroxylase.

PREPARATION EXAMPLE Preparation of2-(2′-naphthylthio)-4-phenyl-4-oxobutanoic acid (Compound Ih-1)

7.04 g (0.04 mol) of commercial 3-benzoylacrylic acid are dissolved in90 mL of methylene chloride. 2-Naphthalenethiol (0.04 mol; 1 equivalent)is then added. The reaction medium is left for 20 hours at 20° C. andthen concentrated under vacuum. The crude solid product isolated is thentriturated from isopropyl ether, filtered off by suction andrecrystallised from isopropyl ether.

Isolated weight: 5.55 g; yield=41%; melting point=146-149° C. (capillarymelting point).

Proton NMR (200 MHz, solvent: deuterated DMSO): 3.74 ppm, multiplet, 2H;4.43 ppm, broad singlet, 1H; 7.9 ppm, multiplet, 12H arom.; 12.9 ppm,COOH).

Infrared spectrometry (cm⁻¹): 1702.8; 1680.7; 1595.0; 1435.2; 1326.6;1217.6.

TLC Analysis:

silica, eluent: methylcyclohexane, ethyl acetate, acetic acid (50/45/5):Rf: 0.53.

The compounds of the family (Ih) as defined above were preparedaccording to a similar process.

Preparation of ethyl 2-(4-methoxyphenylthio)-4-phenyl-4-oxobutanoate(Compound Ih-13)

0.408 g of commercial ethyl benzoylacrylate (0.002 mol) is dissolved in6 ml of methylene chloride in a round-bottomed flask under argon. 0.2809 (1 equivalent) of 4-methoxythiophenol is then added.

The reaction medium is left at 20° C. for 72 hours and then concentratedunder vacuum.

The crude oil isolated is then purified on a column of silica (eluent:90/10 cyclohexane/ethyl acetate).

Isolated weight: 0.390 g; yield=56.6%; oil.

Proton NMR (200 MHz, Solvent: Deuterated Chloroform):

1.06 ppm, triplet, 3H; 3.41 ppm, multiplet, 2H; 3.66 ppm, singlet, 3H;4.01 ppm, multiplet, 3H; 6.72 ppm, doublet, 2H arom.; 7.32 ppm,multiplet, 5H arom.; 7.78 ppm, doublet, 2H arom.

Infrared spectrometry (cm⁻¹): 1730.6; 1685.1; 1493.9; 1448.8; 1287.6;1248.21; 1213.6.

The ethyl ester compounds of family Ih as defined above were preparedaccording to a similar process.

The compounds of family Ih are collated in Tables I 1-4 below. Thepurities were determined by HPLC/MS. TABLE I-1 Compounds Ih

Purity Yield m.p. (° C.); R-SH Number Mass (%) (%) (solvent*)

1h 366.41 99 81.1 146-149 (isopropyl ether)

2h 286.35 99 67.6 132-135 (ethanol 85)

3h 304.34 99 68.4 114‥116 (isopropyl ether)

4h 320.8 99 72.5 140-142 (ethanol 85)

5h 300.38 99 66 132-134 (ethanol 95)

6h 316.38 99 77.2 116-118 (ethanol 50)

7h 292.4 99 6.8 117 (ethanol 50)

8h 300.38 99 52.7 143-146 (ethanol 95)*recrystallisation solvent

TABLE I-2 Compounds Ih

Purity Yield m.p. (° C.); R-SH Number Mass (%) (%) (solvent*)

 9h 341.41 99 33 oil

10h 332.4 97.4 24 oil

11h 348.85 95.2 19.8 oil

12h 328.43 94.4 24.2 oil

13h 344.43 95.7 56.6 oil

14h 364.47 94 9.6 oil

15h 320.42 99 75.8 oil

16h 328.43 99 41.2 oil

TABLE I-3 Compounds Ih

Purity Yield m.p. (° C.); R-SH Number Mass (%) (%) (solvent*)

17h 316.38 99 70.4 121-125 (ethanol 50)

18h 334.37 98.2 51.3 108-110 (ethanol 50)

19h 350.82 99 68 120-121 (ethanol 50)

20h 330.41 99 23.2 137-141 (ethanol 70)

21h 346.4 99 68 137-140 (ethanol 70)

22h 366.44 99 87.4 169-169 (ethanol 50)

23h 322.43 96.7 30.4 120-122 (ethanol 50)

24h 330.41 91.8 72.5 105-109 (ethanol 50)

TABLE I-4 Compounds Ih

Purity Yield m.p. (° C.); R-SH Number Mass (%) (%) (solvent*)

25h 320.8 98.5 78.5 166-169 (ethanol 85)

26h 338.79 98.6 81.2 140-141 (ethanol 85)

27h 355.24 97.8 82.8 154-156 (ethanol 85)

28h 334.82 99 62.9 151-153 (ethanol 85)

29h 350.82 99 54.2 117-119 (ethanol 70)

30h 370.86 96.6 82.7 141-145 (isopropyl ether)

Study of the Inhibitory Activity on Kynurenine 3-Hydroxylase in RatLiver

Experimental Protocol

Rat livers are homogenised (1:8 weight/volume) in a buffer solutioncomprising: 0.25 M sucrose; 50 mM pH 7.4 Tris; 1 mM EDTA; and 1 mM DTT.

The homogenates are centrifuged for 10 minutes at 12000 rpm. The pelletsare resuspended in the buffer solution described above (1:2weight/volume).

The kynurenine 3-hydroxylase inhibition is determined by incubating 10μL of the homogenate with NADPH (2 mM), kynurenine (100 μM) and variousconcentrations of the test compounds in a final volume of 100 μL at 37°C. for 5 minutes.

The compounds are tested at concentrations of between 1 μM and 300 μM.3,4-Dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide is acompound from the company Hoffmann-LaRoche (Basle, see J. Med. Chem., 40(1997), 4738). 30H-Kynurenine was tested according to the protocoldescribed by Carpendo et al. (Neuroscience, 61 (1994), 237-244).

Results:

Each of the experiments is repeated once and the IC₅₀ values (in μmol/L)are calculated and given in the form of a mean of these two experiments.

By way of example, (R)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid(compound i) has an IC₅₀ value of 1±0.2 μmol/L, whereas3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide(compound k) has an IC₅₀ value of 10±2.1 μmol/L.

Results concerning representative examples of family Ih are given inTable II below, in which is indicated the measurement of the percentageof remaining kynurenine 3-hydroxylase activity relative to the control(100%).

Kynurenine 3-hydroxylase inhibition R-SH Ih 10 μM % control

Ih-1 23.2

Ih-2 70.4

Ih-3 50.4

Ih-4 34.8

Ih-5 45.4

Ih-7 81.3

Ih-8 68.6

Kynurenine 3-hydroxylase inhibition R-SH Ih 10 μM % control

Ih-9  80.8

Ih-10 66.7

Ih-11 44.6

Ih-12 63.3

Ih-13 55.2

Ih-14 30.0

Ih-15 95.0

Ih-16 84.4

Kynurenine 3-hydroxylase inhibition R-SH Ih 10 μM % control

Ih-17 16.0

Ih-18 6.6

Ih-19 4.1

Ih-20 13.3

Ih-21 17.4

Ih-22 8.5

Ih-23 38.1

Ih-24 18.9

Kynurenine 3-hydroxylase inhibition R-SH Ih 10 μM % control

Ih-25 67.6

Ih-26 55.5

Ih-27 34.9

Ih-28 50.5

Ih-30 24.3

Study of the Antidiabetic Activity in N0STZ Rats

The antidiabetic activity of the compounds of the formulae (I) and (II)orally was determined on an experimental model of non-insulin-dependentdiabetes, induced in rats with steptozotocin.

The model of non-insulin-dependent diabetes is obtained in the rats bymeans of a neonatal injection (on the day of birth) of steptozotocin.

The diabetic rats used are eight weeks old. The animals are housed, fromthe day of birth to the day of the experiment, in an animal house at aregulated temperature of 21 to 22° C. and subjected to a fixed cycle oflight (from 7 a.m. to 7 p.m.) and darkness (from 7 p.m. to 7 a.m.).Their food consisted of a maintenance diet, and water and food weregiven “ad libitum”, with the exception of fasting two hours before thetests, during which period the food is removed (post-absorptive state).

The rats are treated orally for one (D1) or four (D4) days with the testproduct. Two hours after the final administration of the product and 30minutes after anaesthetising the animals with pentobarbital sodium(Nembutal®), a 300 μL blood sample is taken from the end of the tail.

Among the compounds of the formula (I), the compounds of the family(Ih), especially the compounds of the subfamily (Ii), in particularcompound Ih-1 defined previously(2-(2′-naphthylthio)-4-phenyl-4-oxobutanoic acid) and compound Ih-3 ofthe subfamily (Ij) (2-(4′-fluorophenylthio)-4-phenyl-4-oxobutanoic acid)were evaluated according to the experimental protocol described above.

The results presented below are expressed as a percentage change in theglycaemia on D1 and D4 (number of days of treatment) relative to D0(before the treatment). Compound D1 (20 mg) D1 (200 mg) D4 (20 mg) D4(200 mg) Ih-3 −3 7 −19 −12 Ih-1 7 10 −12 −21

These results show the efficacy of the compounds, especially of theformula (Ih), in reducing glycaemia in the diabetic animals.

This antidiabetic activity is correlated with an inhibitory effect ofthis family of molecules on kynurenine 3-hydroxylase.

Study of the Effect on Glucose Production By the Liver

Materials and Method:

The hepatocytes are isolated from the liver of Wistar rats fasted for 24hours, according to the method described in Methods Cell Biol., 13(1975), 29-83.

The following two methods were used:

1) The hepatocytes are cultured for 16 to 18 hours in DMEM medium in thepresence of AMP cyclase/dexamethasone at respective concentrations of5×10⁻⁵ M and 5×10⁻⁷ M, with preincubation of the products at the testdoses. After washing in pH 7.4 PBS buffer, the cells are incubated forthree hours at 37° C. in a Krebs/AMPc/DEX buffer at the abovementionedconcentrations. 0.1 μM insulin is used as reference substance. Twoidentical experiments are performed (Table III-1).

2) The hepatocytes are cultured for 16 to 18 hours in RPMI 1640 mediumfree of glucose but supplemented with 1% glutamine, 100 U/mL penicillin,100 mg/mL streptomycin and 7×10⁻⁵ M hydrocortisone hemisuccinate.

After washing in pH 7.4 PBS buffer, the cells are incubated for twohours at 37° C. in a Krebs buffer free of glucose and of insulin,containing lactate/pyruvate (10/1 mM) in the presence or absence of thetest compounds. 10 μM MICA (5-methoxyindole-2-carboxylic acid) is usedas reference substance. Two identical experiments are performed (TableIII-2).

Quantification of the glucose is performed via a calorimetric methodusing glucose oxidase (IL test™ Glucose, Monarch 181633-80). The proteinassay is performed on the rest of the incubation medium via the Lowrymethod (BIO-RAD Dc protein assay, BIO-RAD 5000116).

The results are expressed as nmoles of glucose produced per ng ofproteins. The statistical test used is the t test.

Results:

It was thus demonstrated that tryptophan and kynurenine are powerfulinhibitors of hepatic glucose production in vitro.

Effect of kynurenine 3-hydroxylase inhibitors By way of example,compound Ih-1 (Table III 1-3) and(R)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid (compound i) and(R,S)-2-benzyl-4-(3′,4′-dichlorophenyl)-4-oxobutanoic acid (compound j)(Table IV), two kynurenine 3-hydroxylase inhibitors, were found to bepowerful inhibitors of hepatic glucose production in vitro, as shown bythe following results: TABLE III-1 Products tested on primaryhepatocytes Hepatic Glucose Production stimulated by AMPc/DEX Test HGPProteins Products Concentration % of control % of control Ih-1  1 μM 103113  10 μM 83 117 100 μM 15 85

TABLE III-2 Products tested on primary hepatocytes Hepatic ProductionGlucose Basal Lact/Pyr 2 hours Test HGP Proteins Products Concentration% of control % of control Ih-1  1 μM 110 94  10 μM 127 101 100 μM 75 96

TABLE IV Concentration Hepatic glucose production inhibition Compound(μM) (mmol/mg of protein) (%) MICA 10 67** Compound i 0 101 ± 6  — 1 88± 7 13 10 73 ± 4 28** 100 39 ± 3 62** Compound j 0 101 ± 6  — 1 71 ± 330** 10 50 ± 3 51** 100 35 ± 1 65** Compound k 0 587 ± 12 — 10 605 ± 24 0 100 460 ± 12 22 Kynurenine 0 101 ± 6  — 1 99 ± 5  2 10 97 ± 6  4 10066 ± 4 25** 1000 22 ± 2 78** Tryptophan 0 587 ± 12 — 10 518 ± 8  12 100111 ± 5  81**

Study of the Effect on the Secretion of the Pancreatic Hormones Insulinand Glucagon, in N0STZ Diabetic Rats

Materials and Method:

The pancreas is taken from animals rendered diabetic by injection ofstreptozotocin on the day of birth (Portha et al., Diabetes, 23:889-895; (1974)) and anaesthetised with pentobarbital (Nembutal: 45mg/kg; intraperitoneal route).

The isolation and perfusion of the pancreas were performed according toa modification (Assan et al., Nature, 239 (1972), 125-126) of theprotocol described by Sussman et al. (Diabetes, 15 (1966), 466-472).

The effect of the compounds or of the reference substances is tested for35 minutes (from t=20 minutes to t=55 minutes) in Krebs buffer in theabsence of glucose, and then for 30 minutes (from t =55 minutes to t =85minutes) in the presence of 16.5 mM glucose.

The concentration of the hormones, insulin and glucagon, secreted intothe medium is measured via a competitive radioimmunoassay using thekits: Insulin-CT Cis Bio-International, Schering andGlucagon-10904-Biochem immuno system, respectively.

The results are expressed as the mean ±SEM (standard error of mean) ofseveral experiments. The statistical test used is the Scheffé test.

Results:

Effect of Tryptophan and its Metabolites on the Secretion of Insulin andGlucagon in Perfused Isolated Pancreases from N0 STZ Diabetic Rats

FIG. 1 shows that tryptophan stimulates insulin secretion in aglucose-dependent manner in a diabetic rat pancreas. Similarly, FIG. 2shows that tryptophan stimulates glucagon secretion in aglucose-dependent manner in a diabetic rat pancreas.

Kynurenic acid, like tryptophan, stimulates the secretion of insulin(FIG. 3) and of glucagon (FIG. 4) in a glucose-dependent manner in adiabetic rat pancreas.

FIG. 5 and FIG. 6 show the secretion profile for insulin and glucagon,respectively, stimulated with kynurenine (at 10⁻⁴ M and 10⁻⁵ M) in aglucose-dependent manner in a diabetic rat pancreas. This stimulation issimilar to that obtained with tryptophan and kynurenic acid.

Effect of Kynurenine 3-Hydroxylase Inhibitors on the Secretion ofInsulin and Glucagon in Perfused Isolated Pancreases from N0 STZDiabetic Rats

The kynurenine 3-hydroxylase inhibitors show the same insulin andglucagon secretion profile as for tryptophan, kynurenine and kynurenicacid. This observation may be seen in FIGS. 7 and 8 (stimulation ofinsulin and of glucagon, respectively, with compound i) and in FIGS. 9and 10 (stimulation of insulin and of glucagon, respectively, withcompound k).

Study of the Activity on Isolated Rat Islets

Effect of the chemical compounds on insulin secretion as a function ofthe glucose concentration, in vitro, in isolated islets of Langerhans instatic incubation:

The islets of Langerhans obtained by digestion of exocrine pancreatictissue with collagenase, and then purified on Ficoll gradient, areincubated for 90 minutes in the presence of two concentrations ofglucose, (2.8 mM or 8 mM), in the presence or absence of the chemicalcompound. The insulin secretion is assayed by RIA in the incubationmedium.

The potential of the various chemical compounds to stimulate insulinsecretion is estimated by calculating the stimulation factor*.

A compound stimulates the secretion of insulin if this factor is greaterthan or equal to 130% for a given dose of insulin.${\quad^{*}{NB}\text{:}\quad{stimulation}\quad{factor}} = \frac{\left( {G + {Product}} \right)*100}{G}$where

-   -   G=secretion of insulin (pmol/min. islet) in the presence of        glucose alone    -   G+Product=secretion of insulin (pmol/min. islet) in the presence        of the same concentration of glucose and of the test chemical        compound.

FIG. 11 shows the insulin secretion for compounds Ih-18 and (i) at 10⁻⁵M at glucose concentrations of 2.8 mM and 8 mM.

Study of the Effect on the Increase in the Mass of Beta Cells

Culturing of Rat Foetal Pancreases

Experimental Protocol

Embryonic pancreases are collected on day 12.5 of gestation fromgestating females of the Wistar strain, which have received an overdoseof sodium pentobarbital. The embryos are extracted from the uterus andplaced in phosphate-buffered saline (PBS). The dorsal pancreatic bud isdissected under stereomicroscopy. The separation of the mesenchyme,which inhibits the development of the endocrine pancreas, is performedvia an enzymatic reaction with 0.05% concentrated collagenase A in thesynthetic culture medium RPMI 1640.

The pancreatic epithelia thus isolated are inserted into a collagen gel,which allows three-dimensional culturing to be performed. The pancreasesare cultured in the RPMI 1640 culture medium supplemented with 10%foetal calf serum and 5.5 mM glucose and in the absence (control) or inthe presence of the test compounds. The cultures are maintained at 37°C. in the presence of 5% CO₂ for seven days. The culture medium isrenewed every day.

At the end of the seven days of culturing, the pancreases are isolatedfrom the collagen gels and dissociated into individual cells by means ofa trypsin digestion (0.05% trypsin-EDTA) for three minutes at 37° C. Theenzymatic reaction is quenched by adding RPMI 1640 medium containing 20%foetal calf serum. The cells are washed with the same medium and thenfixed to glass slides using a cytocentrifuge for five minutes at 125×g.The cells are then treated with 4% paraformaldehyde, and then incubatedovernight at 4° C. with guinea pig anti-insulin antibody (1:1 500dilution). After washing several times with PBS, they are incubated withFITC-coupled, rabbit anti-guinea pig IgG (dilution 1:100) for 75 minutesat room temperature. The cells are finally mounted in a medium thatprotects the fluorescence and that contains DAPI for labelling the cellnuclei. On each slide, a minimum of 300 nuclei and the amount of cellsexpressing insulin are counted. The calculation of the amount of betacells represents the proportion of cells expressing insulin to the totalnumber of nuclei counted. An experiment is performed with a minimum offour pancreases per group and each experiment is repeated three times.

FIGS. 12, 13, 14 and 15 represent the amount of beta cells expressinginsulin in the cultured rat foetal pancreatic buds over seven days, withor without test compound. The increase in the number of beta cells ismainly due to stimulation of the neogenesis of these cells from thestems cells.

1. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of amedicament for increasing the number of islets of Langerhans cells. 2.Use of a kynurenine 3-hydroxylase inhibitor according to claim 1, in thecontext of the treatment and/or prevention of diabetes, itscomplications and/or its related pathologies.
 3. Use of a kynurenine3-hydroxylase inhibitor for the manufacture of a medicament for thetreatment of prediabetes.
 4. Use according to claim 3, for which thesaid prediabetes is an insulin-dependent prediabetes.
 5. Use accordingto claim 3, for which the said prediabetes is a non-insulin-dependentprediabetes.
 6. Use of a kynurenine 3-hydroxylase inhibitor for themanufacture of a medicament for the the treatment and/or prevention ofinsulin-dependent diabetes.
 7. Use of a kynurenine 3-hydroxylaseinhibitor for the manufacture of a medicament for the prevention ofnon-insulin-dependent diabetes.
 8. Use of a kynurenine 3-hydroxylaseinhibitor for the manufacture of a medicament for the treatment of earlynon-insulin-dependent diabetes.
 9. Use according to claim 3, for whichthe said treatment or prevention is by increasing the number of isletsof Langerhans cells.
 10. Use of a kynurenine 3-hydroxylase inhibitor incombination with one or more immunosuppressants, for the manufacture ofa medicament for the prevention and/or treatment of insulin-dependentdiabetes.
 11. Use according to claim 1, which is suitable for the saidtreatment and/or the said prevention in the case of a patient with animpairment in the number of islets of Langerhans cells.
 12. Useaccording to claim 11, for which the said patient shows a decrease inthe number of islets of Langerhans cells of at least 40%.
 13. Useaccording to claim 11, for which the said patient shows a decrease inthe number of islets of Langerhans cells of between 50% and 90%.
 14. Useaccording to claim 1, which is suitable for the said treatment and/orthe said prevention in the case of a patient with glucose intolerance.15. Use according to claim 14, for which the said patient presents afasting glycaemia of between 1.10 g/l and 1.26 g/l and a glycaemia aftermeals of between 1.40 g/l and 2 g/l after meals.
 16. Use according toclaim 1, which is suitable for the said treatment and/or the saidprevention in the case of a patient with one or more anti-islets ofLangerhans cells immunological markers.
 17. Use according to claim 16,for which the said marker(s) indicate(s) the existence of an autoimmuneresponse of the body directed against the antigenic markers of thebody's islets of Langerhans cells.
 18. Use according to claim 16, forwhich the said marker(s) is (are) chosen from the anti-islet (ICA),anti-glutamic acid decarboxylase (GAD), anti-tyrosine phosphatase (IA-2)and anti-(pro)insulin (AIA) auto-antibodies, or theanti-carboxypeptidase H, anti-64 kD and anti-heat shock proteinantibodies.
 19. Use according to claim 1, which is suitable for the saidtreatment and/or the said prevention in the case of a patient withinsulin resistance.
 20. Use according to claim 19, for which the saidpatient responds partially or not at all to insulin secreted by the betacells or injected.
 21. Use according to claim 1, for which the saidpatient presents a level of glycated haemoglobin of higher than 7%. 22.Use according to claim 1, for which the said patient has islets ofLangerhans cells showing an anomaly of insulin secretion in response toglucose.
 23. Use according to claim 1, for which the said patientpresents a suppression of the early peak of insulin secretion.
 24. Useaccording to claim 1, for which the said patient shows relatedhyperglycaemia and obesity.
 25. Use according to claim 24, for which thesaid patient suffers from paediatric obesity.
 26. Use according to claim1, which is suitable for the said treatment and/or the said preventionin the case of a patient presenting any diabetic risk factor.
 27. Useaccording to claim 25, for which the said risk factor is chosen fromfamilial history, gestational diabetes, excess weight, obesity,insufficient physical exercise, high blood pressure, a high level oftriglycerides, hyperlipidaemia and inflammation.
 28. Use according toclaim 1, comprising the in vitro treatment of isolated islets ofLangerhans cells with the said kynurenine 3-hydroxylase inhibitor. 29.Process for increasing the number or the insulin-secreting capacity ofislets of Langerhans cells, comprising the in vitro application of akynurenine 3-hydroxylase inhibitor to the said cells.
 30. Pharmaceuticalcomposition comprising a kynurenine 3-hydroxylase inhibitor incombination with one or more immunosuppressants. 31-32. (canceled) 33.Use according to claim 1, for which the said kynurenine 3-hydroxylaseinhibitor is a compound of the general formula (I) or (II):

in which: W represents a divalent radical chosen from the followingradicals:

R¹ represents a radical chosen from linear or branched alkyl containingfrom 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and aheteroaryl radical; R² is chosen from hydrogen, a halogen atom,hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylcarbonyl, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and aheterocyclic radical; R³ is chosen from hydrogen, a halogen atom,hydroxyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl,heteroaryl, cycloalkyl and a heterocyclic radical; R² and R³ togetheralso possibly forming a group ═CR¹⁶R¹⁷; or alternatively togetherforming, with the carbon atom that bears them, a cycloalkyl radical or aheterocyclic radical; R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, heteroaryloxy, —N(R¹²R^(12′)), —N(R¹²)OR¹³, linearor branched alkyl containing from 1 to 14 carbon atoms and optionallysubstituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl and a heterocyclic radical; R⁵, R⁶, R⁷ and R⁸, which may beidentical or different, are chosen, independently of each other, fromhydrogen, a halogen atom, and a nitro, cyano, hydroxyl, trifluoromethyl,alkyl, alkoxy, cycloalkyl or aryl radical; the radicals R⁵ and R⁶, onthe one hand, or R⁶ and R⁷, on the other hand, may also form, togetherwith the carbon atoms to which they are attached, a benzene ringoptionally substituted by one or more groups, which may be identical ordifferent, chosen from a halogen atom, a trifluoromethyl, cyano or nitroradical, an alkyl radical and an alkoxy radical; R⁹ represents hydrogenor an alkyl radical; R¹⁰ is chosen from an alkyl, an aryl and aheteroaryl radical; R¹² and R^(12′), which may be identical ordifferent, are chosen, independently of each other, from hydrogen and analkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical; oralternatively R¹² and R^(12′) may form, together with the nitrogen atomto which they are attached, a monocyclic or bicyclic heterocyclic groupcontaining a total of 5 to 10 atoms, among which 1, 2, 3 or 4 arechosen, independently of each other, from nitrogen, oxygen and sulfur,the said heterocyclic radical also optionally comprising 1, 2, 3 or 4double bonds and optionally being substituted by one or more chemicalgroups, which may be identical or different, chosen from hydroxyl,halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl,heteroaryl, heterocyclic radical and trifluoromethyl; R¹³ is chosen fromhydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl,—N(R¹²R^(12′)) or —N(R¹²)OR¹³ radical; R¹⁴ is chosen from hydrogen, ahalogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl,alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl,heteroaryl, cycloalkyl and a heterocyclic radical; R¹⁴ may also form abond with R², thus forming a double bond between the carbon atomsrespectively bearing the substituents R¹⁴ and R²; or alternatively R¹⁴forms, with R² and with the carbon atoms that bear them, a ringcontaining a total of 3, 4, 5, 6 or 7 carbon atoms, among which 1, 2 or3 may be replaced with an atom chosen from nitrogen, oxygen and sulfur,the said ring possibly comprising one or more unsaturations in the formof (a) double bond(s), and being optionally substituted by one or moreradicals, which may be identical or different, chosen from oxo, alkoxy,alkoxycarbonyl and alkylcarbonyloxy; R¹⁵ is chosen from hydrogen, ahalogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl,alkylcarbonyl, alkoxycarbonyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,cycloalkyloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio,alkynylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclylthio,aryl, heteroaryl, cycloalkyl and a heterocyclic radical; R¹⁴ and R¹⁵also possibly forming, together with the carbon atom that bears them, acycloalkyl radical or a heterocyclic radical; R¹⁶ and R¹⁷, which may beidentical or different, are chosen, independently of each other, fromhydrogen, a halogen atom, an alkyl, aryl, heteroaryl or cycloalkylradical and a heterocyclic radical; or alternatively R¹⁶ and R¹⁷ form,together with the carbon atom that bears them, a cycloalkyl radical or aheterocyclic radical; and R¹¹ is chosen from hydrogen and an alkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orcycloalkylalkyl radical, and any protecting group for an amine function;and also the possible geometrical and/or optical isomers thereof, andpossible tautomeric forms thereof; the solvates and hydrates of thesecompounds; and also the possible salts thereof with a pharmaceuticallyacceptable acid or base, or alternatively the pharmaceuticallyacceptable prodrugs of these compounds. 34-52. (canceled)
 53. Processfor manufacturing a medicament for the the treatment and/or preventionof diabetes, its complications and/or its related pathologies, byincreasing the number of islets of Langerhans cells, in which at leastone compound of the formula (I) or (II) as defined in one of claim 1 issubjected to an in vitro test of inhibition of kynurenine 3-hydroxylase,and the molecules responding positively to the said tests are thenconditioned in the form of a pharmaceutical composition, optionally withaddition of a pharmaceutically acceptable filler or vehicle.
 54. Processfor screening candidate compounds for activity in the prevention ortreatment of diabetes, its complications and/or its related pathologies,by increasing the number of islets of Langerhans cells by inhibitingkynurenine 3-hydroxylase, the said candidates not corresponding toformula (I) or (II) as defined in one of claim 33, in which process thecandidate compounds are subjected to an in vitro test of inhibition ofkynurenine 3-hydroxylase, and the candidate that has respondedpositively to this test is selected.